Significance of HIF-1-active cells in angiogenesis and radioresistance

Harada, Hiroshi; Kizaka‐Kondoh, Shinae; Li, G; Itasaka, Satoshi; Shibuya, Kazuhiko; Inoue, Masahiro; Hiraoka, Masahiro

doi:10.1038/sj.onc.1210556

Cited by 126 publications

(115 citation statements)

References 29 publications

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“…For diaminobenzidine staining of pimonidazole hydrochloride and CD31, the formalin-fixed and paraffinembedded sections were treated with anti-pimonidazole antibody and anti-CD31 antibody respectively, as described earlier (Harada et al, 2007a;Liu et al, 2007;Zeng et al, 2008). For fluorescent double staining of HIF-1a and pimonidazole, the tumour xenografts were embedded in OCT compound and frozen at À801C.…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

“…Indeed, several pre-clinical studies showed that the inhibition of intratumoral HIF-1 activity with an HIF-1 inhibitor, YC-1, significantly enhanced the therapeutic effect of radiation (Moeller et al, 2004). Likewise, the elimination of HIF-1-positive cells from solid tumours with a protein drug, TOP3, or with a gene therapy strategy had radiosensitising effects (Harada et al, 2002(Harada et al, , 2007aLiu et al, 2007). However, the inhibition of intratumoral HIF-1 activity in unsuitable timing may suppress rather than enhance the effect of radiation therapy; in that the inhibition has an anti-angiogenic effect and consequently increases the radioresistant hypoxic fraction (Yeo et al, 2003).…”

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confidence: 99%

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Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

et al. 2009

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Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellent target during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect of radiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes of HIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cells were reoxygenated 6 h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1a and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1a accumulated in the reoxygenated regions 24 h postirradiation. Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increase in tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressed the effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation of HIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation of HIF-1 activity is important for the best therapeutic benefit.

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Section: Immunohistochemical Analysesmentioning

confidence: 99%

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confidence: 99%

Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

et al. 2009

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“…As mentioned above, a high SUV is correlated with an inferior overall patient survival (5-7). It has been noted that the tumor microenvironment of many malignancies contains a hypoxic condition, a condition associated with resistance to anticancer agents and poor prognosis (12)(13)(14). Hypoxia-inducible factor-1· (HIF-1·) was found to be upregulated in a broad range of tumors and is involved in angiogenesis, invasion and altered glucose metabolism (14,15).…”

Section: Introductionmentioning

confidence: 99%

SUVmax of FDG-PET correlates with the effects of neoadjuvant chemoradiotherapy for oral squamous cell carcinoma

Miyawaki

Ikeda²,

Hara³

et al. 2010

Oncol Rep

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Abstract. The aim of this study was to analyze the relationship between the maximum standardized uptake value (SUVmax) of 18F-fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) and the effects of neoadjuvant chemoradiotherapy in oral squamous cell carcinoma (OSCC), and to identify the possible biological background of this association. Thirty-seven patients with OSCC, who underwent preoperative FDG-PET followed by cancer treatment with neoadjuvant chemoradiotherapy, were enrolled in this study. The various histological effects following neoadjuvant chemoradiotherapy were compared to the SUVmax in the primary OSCC. These effects were also compared to the immunohistochemical staining score of hypoxia-inducible factor-1· (HIF-1·), glucose membrane transporter (GLUT)-1 and vascular endothelial growth factor (VEGF) in the biopsy specimen. Furthermore, we analyzed the chemosensitivity of KB-3-1 cells to cisplatin under hypoxic conditions using the MTT assay. A negative correlation was observed between the SUVmax and the histological effects following neoadjuvant chemoradiotherapy (p<0.01). The SUVmax was also correlated with the staining score of HIF-1· (p<0.03), but not with GLUT-1 and VEGF. The mean staining score of HIF-1· in the highly effective group was 2.7±1.1, which was significantly lower than that (3.7±0.9) of the poorly effective group (p<0.05). The cell chemosensitivity assay revealed chemoresistant effects under a hypoxic condition in OSCC. In conclusion, the SUVmax is correlated with the effectiveness of neoadjuvant chemoradiotherapy in OSCC.Our clinical and experimental analyses further suggest a possible association of the upregulation of HIF-1· with chemoradiosensitivity in SCC cells.

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“…clinical and experimental evidence suggests that hypoxic processes in cancer cells contribute to the malignant phenotype and to more aggressive tumor behavior (2). Hypoxia offers resistance to anticancer chemotherapy, as well as a predisposition to increased tumor metastases (3). Investigation of the molecular mechanisms specific to cancer cells under hypoxic conditions is important to provide a basis for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of HIF-1-independent VEGF expression in a hepatocellular carcinoma cell line

et al. 2011

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Abstract. Hypoxia-inducible factor-1 (Hif-1) is a master transcription factor that plays a central role in the hypoxic expression of various genes. Vascular endothelial growth factor (VeGf), a known target gene of Hif-1α, has been shown to be induced by hypoxia through a Hif-1α-independent pathway. Hif-1α dominant-negative lentiviral vectors were introduced to decrease the expression of Hif in Hep3B cells. cells were incubated under normoxic or hypoxic conditions. We performed a VeGf enzyme-linked immunosorbent assay (eliSa) using cell culture supernatants, and Western blotting using cell lysates. to validate signaling via Hif-1-dependent or Hif-1-independent pathways, we treated cells with an extracellular signal-regulated kinase (erK) kinase inhibitor, a phosphoinositide 3-kinase (Pi3K) inhibitor, and transfected cells with siSP1. Hif-1α protein expression was induced and the levels of VeGf increased under hypoxic conditions. cells were transfected with siHif-1α and incubated under normoxic or hypoxic conditions. We found that a significant amount of VeGf was produced by a Hif-1-independent pathway. Pi3K inhibitor treatment and siSP1 transient transfection decreased VeGf expression in siHif-1α-transfected cells. therefore, VeGf regulation in Hep3B cells is primarily controlled by the akt/Pi3K and SP1 pathways and is independent of Hif-1 under hypoxic conditions. Introduction most solid tumors contain hypoxic lesions due to an imbalance in oxygen supply and consumption. under hypoxic conditions, normal cells are unable to tolerate ischemia resulting in cell death. although hypoxia is toxic to both cancer cells and normal cells, cancer cells undergo genetic and adaptive changes that allow them to survive and even proliferate in a hypoxic environment (1). clinical and experimental evidence suggests that hypoxic processes in cancer cells contribute to the malignant phenotype and to more aggressive tumor behavior (2). Hypoxia offers resistance to anticancer chemotherapy, as well as a predisposition to increased tumor metastases (3). Investigation of the molecular mechanisms specific to cancer cells under hypoxic conditions is important to provide a basis for anticancer therapy.Hypoxia-inducible factor-1 (Hif-1) is a transcription factor found in mammalian cells that plays a central role in the hypoxic expression of various genes including vascular endothelial growth factor (VEGF). VEGF is one of the first isolated and the most potent angiogenic factor (4). VeGf has an important role during developmental, physiological and pathological neovascularization (5). VeGf is known to be one of the target genes of Hif-1α.Hepatocellular carcinoma (Hcc) is well known as a hypervascular tumor; however, it is hypovascular in its early stage and the rapid proliferation of tumor cells continuously induces local hypoxia in its advanced stage (6). Pharmacological inhibition of the HIF target, VEGF, has proven to be efficacious as a cancer treatment (7). However, research into how the specific regulation of VEGF in cancer cells is di...

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Significance of HIF-1-active cells in angiogenesis and radioresistance

Cited by 126 publications

References 29 publications

Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

SUVmax of FDG-PET correlates with the effects of neoadjuvant chemoradiotherapy for oral squamous cell carcinoma

Molecular mechanism of HIF-1-independent VEGF expression in a hepatocellular carcinoma cell line

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